Neutrophil dysregulation in sepsis-induced acute lung injury: mechanistic framework and therapeutic targeting by natural products

Abstract

Sepsis-induced acute lung injury (SALI) is an important complication of sepsis associated with substantial morbidity and mortality, yet effective targeted therapies remain limited. Neutrophils are central effectors of innate immunity and play indispensable roles in early antimicrobial defense. However, during sepsis, persistent inflammatory stimulation drives neutrophil dysregulation, leading to excessive pulmonary infiltration, aberrant activation, delayed apoptosis, neutrophil extracellular trap (NET) formation, and immune imbalance, all of which contribute to alveolar-capillary barrier disruption and lung injury progression. Emerging evidence indicates that neutrophil heterogeneity in SALI is shaped by multiple molecular regulators rather than by maturation status alone. Trafficking receptors, activation-associated markers, disease-associated transcriptional states, and intercellular signaling pathways—including CXCR4, CXCR2, CD11b, CD16, CD177, Fth1, Prok2, CD64/CD271, PD-L1, and Notch1-related signaling—collectively regulate neutrophil trafficking, activation, effector responses, and crosstalk with endothelial and immune cells. In this review, we summarize the molecular determinants underlying neutrophil functional heterogeneity and discuss the dual role of neutrophils in host defense and tissue injury in SALI. We also highlight the major mechanisms of neutrophil-mediated lung damage and summarize emerging evidence that natural products can alleviate SALI by modulating neutrophil recruitment, oxidative stress, inflammatory signaling, and NET formation. Targeting neutrophil dysregulation represents a potential therapeutic approach that requires further mechanistic and clinical validation.